Advertisement

First-in-child phase I/II study of the dual mTORC1/2 inhibitor vistusertib (AZD2014) as monotherapy and in combination with topotecan-temozolomide in children with advanced malignancies: arms E and F of the AcSé-ESMART trial

Published:September 17, 2021DOI:https://doi.org/10.1016/j.ejca.2021.08.010

      Highlights

      • Dual mammalian (or mechanistic) target of rapamycin (mTOR) inhibition by vistusertib is well tolerated in the paediatric population.
      • Vistusertib monotherapy and with TOTEM exhibits insufficient antitumour response.
      • mTOR pathway–activating mutations do not sensitise to vistusertib therapy.

      Abstract

      Aim

      Arms E and F of the AcSé-ESMART phase I/II platform trial aimed to define the recommended dose and preliminary activity of the dual mTORC1/2 inhibitor vistusertib as monotherapy and with topotecan-temozolomide in a molecularly enriched population of paediatric patients with relapsed/refractory malignancies. In addition, we evaluated genetic phosphatidylinositol 3-kinase (PI3K)/AKT/ mammalian (or mechanistic) target of rapamycin (mTOR) pathway alterations across the Molecular Profiling for Paediatric and Young Adult Cancer Treatment Stratification (MAPPYACTS) trial (NCT02613962).

      Experimental design and results

      Four patients were treated in arm E and 10 in arm F with a median age of 14.3 years. Main diagnoses were glioma and sarcoma. Dose escalation was performed as per the continuous reassessment method, expansion in an Ensign design. The vistusertib single agent administered at 75 mg/m2 twice a day (BID) on 2 days/week and vistusertib 30 mg/m2 BID on 3 days/week combined with temozolomide 100 mg/m2/day and topotecan 0.50 mg/m2/day on the first 5 days of each 4-week cycle were safe. Treatment was well tolerated with the main toxicity being haematological. Pharmacokinetics indicates equivalent exposure in children compared with adults. Neither tumour response nor prolonged stabilisation was observed, including in the 12 patients whose tumours exhibited PI3K/AKT/mTOR pathway alterations. Advanced profiling across relapsed/refractory paediatric cancers of the MAPPYACTS cohort shows genetic alterations associated with this pathway in 28.0% of patients, with 10.5% carrying mutations in the core pathway genes.

      Conclusions

      Vistusertib was well tolerated in paediatric patients. Study arms were terminated because of the absence of tumour responses and insufficient target engagement of vistusertib observed in adult trials. Targeting the PI3K/AKT/mTOR pathway remains a therapeutic avenue to be explored in paediatric patients.

      Clinical trial identifier

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Gatta G.
        • et al.
        Childhood cancer survival in Europe 1999-2007: results of EUROCARE-5--a population-based study.
        Lancet Oncol. 2014; 15: 35-47https://doi.org/10.1016/S1470-2045(13)70548-5
        • Allen C.E.
        • et al.
        Target and agent prioritization for the children's oncology group-national cancer Institute pediatric MATCH trial.
        J Natl Cancer Inst. 2017; 109https://doi.org/10.1093/jnci/djw274
        • Harttrampf A.C.
        • et al.
        Molecular screening for cancer treatment optimization (MOSCATO-01) in pediatric patients: a single-institutional prospective molecular stratification trial.
        Clin Canc Res: Off J Am Assoc Canc Res. 2017; 23: 6101-6112https://doi.org/10.1158/1078-0432.CCR-17-0381
        • Worst B.C.
        • et al.
        Next-generation personalised medicine for high-risk paediatric cancer patients - the INFORM pilot study.
        Eur J Canc. 2016; 65: 91-101https://doi.org/10.1016/j.ejca.2016.06.009
        • Barrett D.
        • Brown V.I.
        • Grupp S.A.
        • Teachey D.T.
        Targeting the PI3K/AKT/mTOR signaling axis in children with hematologic malignancies.
        Paediatr Drugs. 2012; 14: 299-316https://doi.org/10.2165/11594740-000000000-00000
        • Cacchione A.
        • et al.
        Upfront treatment with mTOR inhibitor everolimus in pediatric low-grade gliomas: a single-center experience.
        Int J Canc. 2020; https://doi.org/10.1002/ijc.33438
        • Loh A.H.
        • et al.
        Dissecting the PI3K signaling Axis in pediatric solid tumors: novel targets for clinical integration.
        Front Oncol. 2013; 3: 93https://doi.org/10.3389/fonc.2013.00093
        • Saxton R.A.
        • Sabatini D.M.
        mTOR signaling in growth, metabolism, and disease.
        Cell. 2017; 168: 960-976https://doi.org/10.1016/j.cell.2017.02.004
        • Chandarlapaty S.
        • et al.
        AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity.
        Canc Cell. 2011; 19: 58-71https://doi.org/10.1016/j.ccr.2010.10.031
        • Wan X.
        • Harkavy B.
        • Shen N.
        • Grohar P.
        • Helman L.J.
        Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism.
        Oncogene. 2007; 26: 1932-1940https://doi.org/10.1038/sj.onc.1209990
        • Liao H.
        • et al.
        Dramatic antitumor effects of the dual mTORC1 and mTORC2 inhibitor AZD2014 in hepatocellular carcinoma.
        Am J Canc Res. 2015; 5: 125-139
        • Flannery P.C.
        • et al.
        Preclinical analysis of MTOR complex 1/2 inhibition in diffuse intrinsic pontine glioma.
        Oncol Rep. 2018; 39: 455-464https://doi.org/10.3892/or.2017.6122
        • Zormpas-Petridis K.
        • et al.
        Noninvasive MRI native T1 mapping detects response to MYCN-targeted therapies in the Th-MYCN model of neuroblastoma.
        Canc Res. 2020; 80: 3424-3435https://doi.org/10.1158/0008-5472.CAN-20-0133
        • Pike K.G.
        • et al.
        Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: the discovery of AZD8055 and AZD2014.
        Bioorg Med Chem Lett. 2013; 23: 1212-1216https://doi.org/10.1016/j.bmcl.2013.01.019
        • Pancholi S.
        • et al.
        Combination of mTORC1/2 inhibitor vistusertib plus fulvestrant in vitro and in vivo targets oestrogen receptor-positive endocrine-resistant breast cancer.
        Breast Canc Res. 2019; 21: 135https://doi.org/10.1186/s13058-019-1222-0
        • Kahn J.
        • et al.
        The mTORC1/mTORC2 inhibitor AZD2014 enhances the radiosensitivity of glioblastoma stem-like cells.
        Neuro Oncol. 2014; 16: 29-37https://doi.org/10.1093/neuonc/not139
        • Wong Te Fong A.C.
        • et al.
        Evaluation of the combination of the dual m-TORC1/2 inhibitor vistusertib (AZD2014) and paclitaxel in ovarian cancer models.
        Oncotarget. 2017; 8: 113874-113884https://doi.org/10.18632/oncotarget.23022
        • Basu B.
        • et al.
        First-in-Human pharmacokinetic and pharmacodynamic study of the dual m-TORC 1/2 inhibitor AZD2014.
        Clin Canc Res: Off J Am Assoc Canc Res. 2015; 21: 3412-3419https://doi.org/10.1158/1078-0432.CCR-14-2422
        • Powles T.
        • et al.
        A randomised phase 2 study of AZD2014 versus everolimus in patients with VEGF-refractory metastatic clear cell renal cancer.
        Eur Urol. 2016; 69: 450-456https://doi.org/10.1016/j.eururo.2015.08.035
        • Schmid P.
        • et al.
        Fulvestrant plus vistusertib vs fulvestrant plus everolimus vs fulvestrant alone for women with hormone receptor-positive metastatic breast cancer: the MANTA phase 2 randomized clinical trial.
        JAMA Oncol. 2019; https://doi.org/10.1001/jamaoncol.2019.2526
        • Schmid P.
        • et al.
        A study of vistusertib in combination with selumetinib in patients with advanced cancers: TORCMEK phase Ib results.
        J Clin Oncol. 2017; 35 (2548-2548)https://doi.org/10.1200/JCO.2017.35.15_suppl.2548
        • Bagatell R.
        • et al.
        Phase 1 trial of temsirolimus in combination with irinotecan and temozolomide in children, adolescents and young adults with relapsed or refractory solid tumors: a Children's Oncology Group Study.
        Pediatr Blood Canc. 2014; 61: 833-839https://doi.org/10.1002/pbc.24874
        • Ma D.J.
        • et al.
        A phase II trial of everolimus, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma: NCCTG N057K.
        Neuro Oncol. 2015; 17: 1261-1269https://doi.org/10.1093/neuonc/nou328
        • Andre F.
        • et al.
        Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial.
        Lancet Oncol. 2014; 15: 580-591https://doi.org/10.1016/S1470-2045(14)70138-X
        • Geoerger B.
        • et al.
        Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy.
        Canc Res. 2001; 61: 1527-1532
        • Di Giannatale A.
        • et al.
        Phase II study of temozolomide in combination with topotecan (TOTEM) in relapsed or refractory neuroblastoma: a European Innovative Therapies for Children with Cancer-SIOP-European Neuroblastoma study.
        Eur J Canc. 2014; 50: 170-177https://doi.org/10.1016/j.ejca.2013.08.012
        • Le Teuff G.
        • et al.
        Phase II study of temozolomide and topotecan (TOTEM) in children with relapsed or refractory extracranial and central nervous system tumors including medulloblastoma with post hoc Bayesian analysis: a European ITCC study.
        Pediatr Blood Canc. 2020; 67e28032https://doi.org/10.1002/pbc.28032
        • Basu B.
        • et al.
        Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high-grade serous ovarian and squamous non-small-cell lung cancer.
        Ann Oncol: Off J Eur Soc Med Oncol. 2018; 29: 1918-1925https://doi.org/10.1093/annonc/mdy245
        • Bautista F.
        • et al.
        Revisiting the definition of dose-limiting toxicities in paediatric oncology phase I clinical trials: an analysis from the Innovative Therapies for Children with Cancer Consortium.
        Eur J Canc. 2017; 86: 275-284https://doi.org/10.1016/j.ejca.2017.09.015
        • Schwartz L.H.
        • et al.
        RECIST 1.1-Update and clarification: from the RECIST committee.
        Eur J Canc. 2016; 62: 132-137https://doi.org/10.1016/j.ejca.2016.03.081
        • Wen P.Y.
        • et al.
        Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group.
        J Clin Oncol: Off J Am Soc Clin Oncol. 2010; 28: 1963-1972https://doi.org/10.1200/JCO.2009.26.3541
        • Vicier C.
        • Dieci M.V.
        • Andre F.
        New strategies to overcome resistance to mammalian target of rapamycin inhibitors in breast cancer.
        Curr Opin Oncol. 2013; 25: 587-593https://doi.org/10.1097/CCO.0000000000000014
        • Garcia-Garcia C.
        • et al.
        MEK plus PI3K/mTORC1/2 therapeutic efficacy is impacted by TP53 mutation in preclinical models of colorectal cancer.
        Clin Canc Res: Off J Am Assoc Canc Res. 2015; 21: 5499-5510https://doi.org/10.1158/1078-0432.CCR-14-3091
        • Lapointe S.
        • et al.
        A phase I study of vistusertib (dual mTORC1/2 inhibitor) in patients with previously treated glioblastoma multiforme: a CCTG study.
        Invest N Drugs. 2020; 38: 1137-1144https://doi.org/10.1007/s10637-019-00875-4
        • Unni N.
        • Arteaga C.L.
        Is dual mTORC1 and mTORC2 therapeutic Blockade clinically feasible in cancer?.
        JAMA Oncol. 2019; 5: 1564-1565https://doi.org/10.1001/jamaoncol.2019.2525
        • Gremke N.
        • et al.
        mTOR-mediated cancer drug resistance suppresses autophagy and generates a druggable metabolic vulnerability.
        Nat Commun. 2020; 11: 4684https://doi.org/10.1038/s41467-020-18504-7
        • Guri Y.
        • Hall M.N.
        mTOR signaling confers resistance to targeted cancer drugs.
        Trends Canc. 2016; 2: 688-697https://doi.org/10.1016/j.trecan.2016.10.006
        • Jiang B.H.
        • Liu L.Z.
        Role of mTOR in anticancer drug resistance: perspectives for improved drug treatment.
        Drug Resist Updates. 2008; 11: 63-76https://doi.org/10.1016/j.drup.2008.03.001
        • Wong C.H.
        • Siah K.W.
        • Lo A.W.
        Estimation of clinical trial success rates and related parameters.
        Biostatistics. 2019; 20: 273-286https://doi.org/10.1093/biostatistics/kxx069
        • Grobner S.N.
        • et al.
        The landscape of genomic alterations across childhood cancers.
        Nature. 2018; 555: 321-327https://doi.org/10.1038/nature25480
        • Hillmann P.
        • Fabbro D.
        PI3K/mTOR pathway inhibition: opportunities in oncology and rare genetic diseases.
        Int J Mol Sci. 2019; 20https://doi.org/10.3390/ijms20225792
        • Kwiatkowski D.J.
        • et al.
        Mutations in TSC1, TSC2, and MTOR are associated with response to rapalogs in patients with metastatic renal cell carcinoma.
        Clin Canc Res: Off J Am Assoc Canc Res. 2016; 22: 2445-2452https://doi.org/10.1158/1078-0432.CCR-15-2631
        • Zhang Y.
        • et al.
        A pan-cancer proteogenomic Atlas of PI3K/AKT/mTOR pathway alterations.
        Canc Cell. 2017; 31 (820–832.e823)https://doi.org/10.1016/j.ccell.2017.04.013